scholarly journals Insulin resistance in soleus muscle from obese Zucker rats. Involvement of several defective sites

1980 ◽  
Vol 186 (2) ◽  
pp. 525-534 ◽  
Author(s):  
Marco Crettaz ◽  
Marc Prentki ◽  
Daniel Zaninetti ◽  
Bernard Jeanrenaud
Keyword(s):  
Insulin Resistance ◽  
Glucose Metabolism ◽  
Glucose Transport ◽  
Insulin Binding ◽  
Zucker Rats ◽  
Maximal Response ◽  
Endogenous Fatty Acid ◽  
Lipid Utilization ◽  
Obese Rats ◽  
Obese Zucker Rats

1. The effect of insulin upon glucose transport and metabolism in soleus muscles of genetically obese (fa/fa) and heterozygote lean Zucker rats was investigated at 5–6 weeks and 10–11 weeks of age. Weight-standardized strips of soleus muscles were used rather than the intact muscle in order to circumvent problems of diffusion of substrates. 2. In younger obese rats (5–6 weeks), plasma concentrations of immunoreactive insulin were twice those of controls, whereas their circulating triacylglycerol concentrations were normal. Insulin effects upon 2-deoxyglucose uptake and glucose metabolism by soleus muscles of these rats were characterized by both a decreased sensitivity and a decrease in the maximal response of this tissue to the hormone. 3. In older obese rats (10–11 weeks), circulating concentrations of insulin and triacylglycerols were both abnormally elevated. A decrease of 25–35% in insulin-binding capacity to muscles of obese rats was observed. The soleus muscles from the older obese animals also displayed decreased sensitivity and maximal response to insulin. However, at a low insulin concentration (0.1m-i.u./ml), 2-deoxyglucose uptake by muscles of older obese rats was stimulated, but such a concentration was ineffective in stimulating glucose incorporation into glycogen, and glucose metabolism by glycolysis. 4. Endogenous lipid utilization by muscle was calculated from the measurements of O2 consumption, and glucose oxidation to CO2. The rate of utilization of fatty acids was normal in muscles of younger obese animals, but increased in those of the older obese rats. Increased basal concentrations of citrate, glucose 6-phosphate and glycogen were found in muscles of older obese rats and may reflect intracellular inhibition of glucose metabolism as a result of increased lipid utilization. 5. Thus several abnormalities are responsible for insulin resistance of muscles from obese Zucker rats among which we have observed decreased insulin binding, decreased glucose transport and increased utilization of endogenous fatty acid which could inhibit glucose utilization.

Physical training of lean and genetically obese Zucker rats: effect on fat cell metabolism

1982 ◽  
Vol 243 (5) ◽  
pp. E418-E426 ◽  
Author(s):  
L. J. Wardzala ◽  
M. Crettaz ◽  
E. D. Horton ◽  
B. Jeanrenaud ◽  
E. S. Horton
Keyword(s):  
Glucose Metabolism ◽  
Glucose Transport ◽  
Cell Metabolism ◽  
Insulin Binding ◽  
Zucker Rats ◽  
Fat Cell ◽  
Obese Rats ◽  
Increased Sensitivity ◽  
Obese Zucker Rats ◽  
Adipose Cells

The effects of 6-wk treadmill training program on the metabolism of isolated adipose cells from obese (fa/fa) and lean (Fa/?) Zucker rats were studied. Glucose metabolism and transport, insulin binding, and lipolysis were measured in adipose cells prepared from sedentary control and exercise-trained (ET) lean and/or obese rats. Two- to threefold increases in glucose metabolism were observed in cells from lean and obese ET rats compared with their respective controls. However, the insulin concentrations giving half-maximal stimulation (measuring insulin sensitivity) did not change (approximately 8 microunits/ml in lean and approximately 45 microunits/ml in obese rats). In lean ET rats, glucose transport and maximal glucose metabolic capacity (transport not rate-limiting) were increased twofold and sensitivity of lipolysis to epinephrine was increased three- to fourfold. These were not measured in obese rats. The results suggest that training of both lean and obese Zucker rats increases glucose utilization in adipose cells by increasing both glucose transport and intracellular glucose metabolism. Increased triglyceride turnover is also suggested by the increased sensitivity of lipolysis to epinephrine.

scholarly journals Changes in content and secretion of pancreatic enzymes in the obese Zucker rat

1984 ◽  
Vol 219 (1) ◽  
pp. 333-336 ◽  
Author(s):  
R Bruzzone ◽  
E R Trimble ◽  
A Gjinovci ◽  
A E Renold
Keyword(s):  
Insulin Resistance ◽  
Glucose Metabolism ◽  
Digestive Enzymes ◽  
Enzyme Secretion ◽  
Zucker Rats ◽  
Zucker Rat ◽  
Obese Zucker Rat ◽  
Obese Rats ◽  
Old Rats ◽  
Obese Zucker Rats

The contents of three major digestive enzymes (amylase, lipase and chymotrypsinogen) were measured in the obese Zucker rat. Only minimal changes were found in 7-week-old rats, but in adult obese rats (14-16 weeks) the amylase content was decreased by 50%, whereas the lipase and chymotrypsinogen contents were increased by 45% and 20%, respectively, compared with lean controls. Abnormalities of enzyme secretion were also found. Since the changes observed in enzyme proportions in adult obese Zucker rats are qualitatively similar to those observed in insulinopenic diabetes and other states associated with decreased glucose metabolism, it is speculated that the abnormalities found in the obese Zucker rat may be due to decreased glucose metabolism in the exocrine tissue consequent to insulin resistance.

Molecular analysis of insulin resistance in isolated ventricular cardiomyocytes of obese Zucker rats

1997 ◽  
Vol 273 (1) ◽  
pp. E59-E67 ◽  
Author(s):  
T. Kolter ◽  
I. Uphues ◽  
J. Eckel
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Zucker Rats ◽  
Glut 4 ◽  
Ventricular Cardiomyocytes ◽  
Obese Rats ◽  
Glut 4 Translocation ◽  
Obese Zucker Rats

Isolated ventricular cardiomyocytes obtained from lean and genetically (fa/fa) obese Zucker rats were used to correlate alterations of insulin-induced glucose transport activation and GLUT-4 translocation to possible defects of the insulin signaling cascade. Maximal stimulation with insulin was found to produce an unaltered translocation of GLUT-4 to the plasma membrane (4.2- and 3.7-fold increase for lean and obese rats, respectively). However, a largely reduced sensitivity of 3-O-methylglucose transport could be detected in obese rats at physiological doses of insulin (completely unresponsive at 8 x 10(-11) M compared with 3-fold stimulation of glucose transport in lean controls). Tyrosine phosphorylation of the insulin receptor beta-subunit and the insulin receptor substrate 1 (IRS-1) was stimulated identically in cardiomyocytes from both lean and obese rats. Labeling of cells with [33P]orthophosphate revealed a marked increase in the serine and/or threonine phosphorylation of IRS-1 in the obese group (370% of lean controls), with a concomitant reduction in IRS-1 abundance (30-40%). The reduced sensitivity of glucose transport at 8 x 10(-11) M insulin was then found to correlate to a completely blunted response of IRS-1-associated phosphatidylinositol 3-kinase activity in cardiomyocytes from obese rats. Those data show that cardiac insulin resistance of obesity involves defective insulin signaling at low concentrations of the hormone, whereas GLUT-4 translocation is fully operative in the isolated cell. It is suggested that hyperphosphorylation of IRS-1 may significantly contribute to the pathogenesis of insulin resistance in the heart.

Glucose transport: locus of muscle insulin resistance in obese Zucker rats

1988 ◽  
Vol 255 (3) ◽  
pp. E374-E382 ◽  
Author(s):  
W. M. Sherman ◽  
A. L. Katz ◽  
C. L. Cutler ◽  
R. T. Withers ◽  
J. L. Ivy
Keyword(s):  
Insulin Resistance ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Glycogen Synthase ◽  
Fiber Type ◽  
Zucker Rats ◽  
Muscle Insulin Resistance ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Fast Twitch

The purposes of this study were to determine whether the muscle insulin resistance of the obese rat is due to a defect in the glucose transport process and whether the insulin resistance is fiber-type specific. The hindlimbs of fasted, 14-wk-old obese (fa/fa) and lean (fa/?) Zucker rats were perfused with perfusate containing 8 mM glucose and no insulin or 8 mM glucose and either a physiological (0.15 mU/ml), a submaximal (1.50 mU/ml), or a maximal (15.0 mU/ml) insulin concentration. Glucose uptake was determined after which the initial rate of glucose transport was determined using 3-O-methyl-D-glucose (3-OMG). Glucose uptake of the obese rats was depressed by 40, 33, 42, and 47% in the absence of insulin and in the presence of the physiological, submaximal, and maximal insulin concentrations, respectively, when compared with lean littermates. Glucose transport in the absence and in the presence of the three insulin concentrations was significantly lower in the soleus (slow-twitch, oxidative fibers), red quadriceps (fast-twitch, oxidative, glycolytic fibers), and gastrocnemius (mixed fibers) of the obese rats when compared with lean rats. Glucose transport in the white quadriceps (fast-twitch, glycolytic fibers) was significantly lower in the obese rats in the absence of insulin and in the presence of the submaximal and maximal insulin concentrations. The glycogen concentration and the activity of hexokinase were the same and the glycogen synthase activity was higher in the muscles for the obese rats when compared to lean rats.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Plasma calcitonin gene-related peptide is increased prior to obesity, and sensory nerve desensitization by capsaicin improves oral glucose tolerance in obese Zucker rats

2005 ◽  
Vol 153 (6) ◽  
pp. 963-969 ◽  
Author(s):  
Dorte X Gram ◽  
Anker J Hansen ◽  
Michael Wilken ◽  
Torben Elm ◽  
Ove Svendsen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Sensory Nerve ◽  
Zucker Rats ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Nerve Activity ◽  
Calcitonin Gene ◽  
Obese Rats ◽  
Obese Zucker Rats

Objective: It has earlier been demonstrated that capsaicin-induced desensitization improves insulin sensitivity in normal rats. However, whether increased capsaicin-sensitive nerve activity precedes the onset of insulin resistance in diet-induced obesity – and therefore might be involved in the pathophysiology – is not known. Further, it is of relevance to investigate whether capsaicin desensitization improves glycaemic control even in obese individuals and we therefore chose the obese Zucker rats to test this. Design and methods: Plasma levels of calcitonin gene-related peptide (CGRP; a marker of sensory nerve activity) was assessed in 8-week-old Zucker rats. To investigate whether capsaicin desensitization (100 mg/kg at 9 weeks of age) would also ameliorate glycaemia in this non-diabetic model, we assessed oral glucose tolerance at 7 weeks after capsaicin. Results: It was found that plasma CGRP levels were elevated in obese Zucker rats prior to the onset of obesity (16.1±3.4 pmol/l in pre-obese Zucker rats vs 6.9±1.1 pmol/l in lean littermates; P = 0.015) despite similar body weights. Furthermore, capsaicin desensitization reduced both fasting blood glucose (4.3±0.2 mmol/l vs 5.1±0.2 mmol/l in controls; P = 0.050) as well as the mean blood glucose level during an oral glucose tolerance test (OGTT) (6.8±0.3 mmol/l vs 8.6±0.5 mmol/l in control obese rats; P = 0.024) whereas the plasma insulin levels during the OGTT were unchanged. However this did not lead to an improvement in insulin resistance or to a reduction of tissue triglyceride accumulation in muscle or liver. Conclusion: We concluded that capsaicin-induced sensory nerve desensitization improves glucose tolerance in Zucker rats. Since, in this study, plasma CGRP levels, a marker of sensory nerve activity, were increased in the pre-obese rats, our data support the hypothesis that increased activity of sensory nerves precedes the development of obesity and insulin resistance in Zucker rats.

scholarly journals Effects of an adenosine-receptor antagonist on insulin-resistance in soleus muscle from obese Zucker rats

1984 ◽  
Vol 221 (3) ◽  
pp. 915-917 ◽  
Author(s):  
R A Challis ◽  
L Budohoski ◽  
B McManus ◽  
E A Newsholme
Keyword(s):  
Insulin Resistance ◽  
Receptor Antagonist ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Glucose Utilization ◽  
Glycogen Synthesis ◽  
Zucker Rats ◽  
Adenosine Receptor Antagonist ◽  
Obese Rats ◽  
Obese Zucker Rats

The decreased sensitivity of glycolysis to insulin seen in isolated soleus muscles from genetically obese Zucker rats was abolished by addition of the adenosine-receptor antagonist 8-phenyltheophylline to the incubation medium; 8-phenyltheophylline had no effect on the sensitivity of glycogen synthesis to insulin. These findings suggest that changes in the sensitivity of glucose utilization by muscles of genetically obese rats may be explained, in part, by a modification in either the concentration of adenosine or the affinity of adenosine receptors in skeletal muscle.

scholarly journals Chronic renin inhibition with aliskiren improves glucose tolerance, insulin sensitivity, and skeletal muscle glucose transport activity in obese Zucker rats

2012 ◽  
Vol 302 (1) ◽  
pp. R137-R142 ◽  
Author(s):  
Elizabeth M. Marchionne ◽  
Maggie K. Diamond-Stanic ◽  
Mujalin Prasonnarong ◽  
Erik J. Henriksen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Transport ◽  
Insulin Action ◽  
Whole Body ◽  
Zucker Rats ◽  
Obese Zucker Rats ◽  
Renin Inhibition

We have demonstrated previously that overactivity of the renin-angiotensin system (RAS) is associated with whole body and skeletal muscle insulin resistance in obese Zucker ( fa/fa) rats. Moreover, this obesity-associated insulin resistance is reduced by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor (type 1) blockers. However, it is currently unknown whether specific inhibition of renin itself, the rate-limiting step in RAS functionality, improves insulin action in obesity-associated insulin resistance. Therefore, the present study assessed the effect of chronic, selective renin inhibition using aliskiren on glucose tolerance, whole body insulin sensitivity, and insulin action on the glucose transport system in skeletal muscle of obese Zucker rats. Obese Zucker rats were treated for 21 days with either vehicle or aliskiren (50 mg/kg body wt ip). Renin inhibition was associated with a significant lowering (10%, P < 0.05) of resting systolic blood pressure and induced reductions in fasting plasma glucose (11%) and free fatty acids (46%) and homeostatic model assessment for insulin resistance (13%). Glucose tolerance (glucose area under the curve) and whole body insulin sensitivity (inverse of the glucose-insulin index) during an oral glucose tolerance test were improved by 15% and 16%, respectively, following chronic renin inhibition. Moreover, insulin-stimulated glucose transport activity in isolated soleus muscle of renin inhibitor-treated animals was increased by 36% and was associated with a 2.2-fold greater Akt Ser473 phosphorylation. These data provide evidence that chronic selective inhibition of renin activity leads to improvements in glucose tolerance and whole body insulin sensitivity in the insulin-resistant obese Zucker rat. Importantly, chronic renin inhibition is associated with upregulation of insulin action on skeletal muscle glucose transport, and it may involve improved Akt signaling. These data support the strategy of targeting the RAS to improve both blood pressure regulation and insulin action in conditions of insulin resistance.

scholarly journals Dehydroepiandrosterone Decreases Serum Tumor Necrosis Factor-α and Restores Insulin Sensitivity: Independent Effect from Secondary Weight Reduction in Genetically Obese Zucker Fatty Rats*

Endocrinology ◽  
1998 ◽  
Vol 139 (7) ◽  
pp. 3249-3253 ◽  
Author(s):  
Mari Kimura ◽  
Shun-ichi Tanaka ◽  
Yoshihiko Yamada ◽  
Yoshihiro Kiuchi ◽  
Tadashi Yamakawa ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Tumor Necrosis ◽  
Zucker Rats ◽  
Tnf Α ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Dhea Treatment ◽  
Necrosis Factor

Abstract Dehydroepiandrosterone (DHEA) and its sulfate ester are the most abundant circulating adrenal steroids in humans. Administration of DHEA has been reported to have beneficial effects on obesity, hyperlipidemia, diabetes, and atherosclerosis in obese rodents, although its effects on insulin resistance have not been fully elucidated. In this study, the effects of DHEA treatment on insulin sensitivity were investigated in genetically obese Zucker rats, an animal model of insulin resistance, using the euglycemic clamp technique. After 0.4% DHEA was administered for 10 days to female obese Zucker rats aged 16 weeks, body weight and plasma insulin decreased and glucose disposal rate (GDR), which was normally reduced in obese rats, rose significantly compared with age- and sex-matched control obese rats. On the other hand, although the pair-fed obese rats also showed levels of weight reduction similar to those of DHEA-treated rats, the increase in GDR of DHEA-treated rats was significantly greater than in pair-fed rats, suggesting a direct ameliorating effect of DHEA on insulin sensitivity of obese rats. Serum concentration of tumor necrosis factor (TNF)-α, one of cytokines causing insulin resistance, was also reduced significantly in DHEA-treated, but not in pair-fed obese rats. In conclusion, our results suggest that DHEA treatment reduces body weight and serum TNF-α independently, and that both may ameliorate insulin resistance in obese Zucker fatty rats.

Insulin sensitizer YM268 ameliorates insulin resistance by normalizing the decreased content of GLUT4 in adipose tissue of obese Zucker rats

1997 ◽  
pp. 693-700 ◽  
Author(s):  
A Shimaya ◽  
O Noshiro ◽  
R Hirayama ◽  
T Yoneta ◽  
K Niigata ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Transporter ◽  
Zucker Rats ◽  
Epididymal Adipose Tissue ◽  
Maximum Effect ◽  
Insulin Sensitizer ◽  
Peripheral Insulin Resistance ◽  
Obese Rats ◽  
Obese Zucker Rats

Genetically obese Zucker rats exhibit mild hyperglycaemia and hyperinsulinaemia suggesting the existence of peripheral insulin resistance. We have examined the effects of YM268, an analogue of thiazolidinedione, on the content and translocation of a glucose transporter (GLUT4) in epididymal adipose tissue in 11-week-old obese and lean Zucker rats. The administration of YM268 at a dose of 10 mg/kg for 2 weeks ameliorated hyperglycaemia, hyperinsulinaemia, and impaired glucose tolerance after glucose load in obese rats. The GLUT4 content per fat pad in obese rats was reduced to 36% of that in lean littermates. Obese rats treated with YM268 increased GLUT4 concentrations in their fat pads from a basal value of 36% up to 191% of the level in lean rats. Furthermore, in adipocytes prepared from obese rats, an increase in the ratio of GLUT4 in plasma membrane to the total amount of GLUT4 (PM-GLUT4 ratio) induced by the submaximal concentration of insulin (0.3 nmol/l) was significantly attenuated compared with that in lean rats. But the maximum effect of insulin (3 nmol/l) was not attenuated. Meanwhile, YM268 had no significant effect on the attenuated PM-GLUT4 ratio in response to insulin in obese rats. These data suggested that one of the mechanisms by which YM268 improved insulin resistance in obese Zucker rats was to normalize the decreased GLUT4 content in the adipose tissue.

scholarly journals Tissue and isoform-selective activation of protein kinase C in insulin-resistant obese Zucker rats - effects of feeding

1999 ◽  
Vol 162 (2) ◽  
pp. 207-214 ◽  
Author(s):  
X Qu ◽  
JP Seale ◽  
R Donnelly
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Membrane Fraction ◽  
Zucker Rats ◽  
Kinase C ◽  
Pkc Epsilon ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Fasted Rats

The mechanisms of insulin resistance in the obese Zucker rat have not been clearly established but increased diacylglycerol-protein kinase C (DAG-PKC) signalling has been associated with decreased glucose utilisation in states of insulin resistance and non-insulin-dependent diabetes mellitus. The purpose of this study was to characterise tissue- and isoform-selective differences in DAG-PKC signalling in insulin-sensitive tissues from obese Zucker rats, and to assess the effects of feeding on DAG-PKC pathways. Groups of male obese (fa/fa, n=24) and lean (fa/-, n=24) Zucker rats were studied after baseline measurements of fasting serum glucose, triglycerides, insulin and oral glucose tolerance tests. Liver, epididymal fat and soleus muscle samples were obtained from fed and overnight-fasted rats for measurements of DAG, PKC activity and individual PKC isoforms in cytosol and membrane fractions. Obese rats were heavier (488+/-7 vs 315+/-9 g) with fasting hyperglycaemia (10.5+/-0.8 vs 7.7+/-0.1 mM) and hyperinsulinaemia (7167+/-363 vs 251+/-62 pM) relative to lean controls. In fasted rats, PKC activity in the membrane fraction of liver was significantly higher in the obese group (174+/-16 vs 108+/-12 pmol/min/mg protein, P<0.05) but there were no differences in muscle and fat. The fed state was associated with increased DAG levels and threefold higher PKC activity in muscle tissue of obese rats, and increased expression of the major muscle isoforms, PKC-theta and PKC-epsilon: e.g. PKC activity in the membrane fraction of muscle from obese animals was 283+/-42 (fed) vs 107+/-20 pmol/min/mg protein (fasting) compared with 197+/-27 (fed) and 154+/-21 pmol/min/mg protein (fasting) in lean rats. In conclusion, hepatic PKC activity is higher in obese rats under basal fasting conditions and feeding-induced activation of DAG-PKC signalling occurs selectively in muscle of obese (fa/fa) rats due to increased DAG-mediated activation and/or synthesis of PKC-theta and PKC-epsilon. These changes in PKC are likely to exacerbate the hyperglycaemia and hypertriglyceridaemia associated with obesity-induced diabetes.

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